Phosphodiesterases (PDEs) are a family of enzymes that metabolize 3′,5′ cyclic nucleotides to 5′ nucleoside monophosphates, thereby regulating the activity of second messengers such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase type 4 (PDE4), which is a subfamily of cAMP-specific PDE, has generated interest as a target for the development of novel anti-asthmatic and anti-inflammatory compounds. PDE4 is known to exist in at least four isoforms, each of which is encoded by a distinct gene. Each of the four known PDE4 gene products is believed to play varying roles in over forty allergic and/or inflammatory responses. Inhibition of PDE4, and in particular the inhibition of specific isoforms that produce detrimental responses, can beneficially affect allergy and inflammation symptoms. Practical and economical methods providing novel PDE4 inhibitors are therefore highly desirable.
Roflumilast (CAS 162401-32-3) is a member of a class of fluoroalkoxy-substituted benzamides developed by BYK Gulden Lomberg Chemische Fabrik GmbH (see, for example, U.S. Pat. No. 5,712,298). The chemical name ofroflumilast is 3-(cyclopropylmethoxy)-N-(3,5-dichloro-pyridin-4-yl)-4-(difluoromethoxy)benzamide. The compound is indicated to be useful as a PDE4 inhibitor.
WO 95/01338 describes the preparation of dialkyl-substituted benzamides, including roflumilast, and the use thereof as PDE4 inhibitors. Such compounds are also proposed for the treatment of certain disorders of the skin such as dermatoses. WO 2004/033430 describes the preparation of a dialkoxy-substituted benzoyl compound which can be further converted to dialkoxy-substituted benzamides.
WO 94/02465 and WO 93/25517 describe the preparation of dialkoxy-substituted benzamides. The compounds are obtained by reacting activated benzoic acid derivatives of the general formula:
with amines of the general formula R3NH2. The disclosed benzoic acid derivatives are acid halides, especially acid chlorides, and anhydrides. The reaction takes place in the presence of a base (e.g. an organic base such as triethylamine, N-methylmorpholine, or pyridine; or an alkali metal hydride, such as sodium hydride) in an inert solvent.
WO 2004/080967 describes the preparation of dialkoxy-substituted benzamides from dialkoxy-substituted benzoic acid and the anion of 4-amino-3,5-dichloropyridine. Roflumilast is prepared using the anion of 4-amino-3,5-dichloropyridine (Scheme 1, Formula 1, below) and an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid that contains a suitable leaving group (Scheme 1, Formula 2, below). The use of a strong base, such as KOtBu, NaOtBu, or LiOtBu, is necessary to prepare the anion 1, and the reaction temperature must be maintained between 15 and 30° C. The preparation of benzoic acid derivative 2, where LG is a chloride leaving group, requires 1-4 equivalents of thionyl chloride for reaction with 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl acid at 70-90° C. The coupling of 1 and 2 is carried out at 20-30° C. in DMF.

WO 2004/033430 describes the preparation of a dialkoxy-substituted benzoyl compound which can be further converted to dialkoxy-substituted benzamides, including roflumilast, using carbonylation technology. The key intermediates, including 3-cyclopropyl methoxy-4-difluoromethoxybenzoic acid and its derivatives (as disclosed in WO 2004/080967), are derived via carbonylation of 1-halo-3-cyclopropylmethoxy-4-difluoromethoxybenzene.
Although processes for roflumilast preparation have been disclosed as discussed above, none of the known methods are environmentally friendly. The known processes are either environmentally harmful or used in harsh conditions. WO 95/01338, for example, describes the preparation of dialkyl-substituted benzamides by making use of thionyl chloride, which is corrosive, explosive and may produce dangerous gases such as sulfur dioxide, and pyrophoric strong bases such as sodium hydride. Meanwhile, WO 2004/080967 describes the preparation of roflumilast by using combustible potassium tert-butoxide (KOtBu). Accordingly, there remains an unmet need for a simple and safe process for industrial preparation of roflumilast and similar benzamides. The practical and economical processes disclosed herein address this need and other needs.